The pathogenesis of glomerular injury in type II diabetes has been the object of remarkably few studies, though this disorder is the most common cause of renal failure in the United States. An ongoing study of the natural history of renal disease in Pima Indians with type II diabetes provides a unique opportunity to relate alterations in glomerular structure and function in this disorder. This study provides for Pima Indians in Arizona to undergo clearance studies to (1) determine the glomerular filtration rate (GFR) and elucidate its determinants; and (2) characterize the abnormality of glomerular barrier function that underlies proteinuria. Initial study of 5 cross-sectional groups, to be comprised of 30-60 subjects each, reveals that GFR is elevated by 14% and that glomerular pore size distribution is shifted to pores of larger radius at approximately 1 year after the onset of type II diabetes (Group 2). With the development of microalbuminuria after a decade of type II diabetes (Group 3), GFR becomes still more elevated, and falls back to the normal range only after albuminuria has increased to above 300 mu(g)/min following several more years of type II diabetes (Group 4). Dextran sieving profiles reveal that a progressive loss of barrier size- selectivity in Groups 3 and 4 attends the increasing magnitude of proteinuria. The purpose of the proposal is to transport 15 members each of Pima Indian Groups 2, 3 and 4 from Arizona to Stanford University for a renal biopsy study. Additional biopsy studies will be performed in Pima Indians with long-term type II diabetes but with normal albumin excretion rates. Glomeruli will be examined with morphometric techniques to determine whether the surface area available for filtration correlates with the computed ultrafiltration coefficient K(f) and thus explains the prevailing GFR. By morphometric analysis of the ultrastructure of the filtration pathway we will also seek to determine whether alterations in extracellular matrix and/or epithelial foot processes can be related to proteinuria and the observed derangement of barrier size-selectivity. A clear understanding of the structural basis of the earliest stages of glomerular injury in type II diabetes will enhance our understanding of it pathogenesis and course. This, in turn, could provide a rational basis for future investigation of therapeutic interventions which show promise of ameliorating the irrevocably progressive course of this disorder.